The broad, long-term objectives of the research proposed for this R21 award are to elucidate the mechanisms by which abnormal glucose metabolism contributes to the pathophysiology of treatment resistance in bipolar mood disorder (BPD) and eventually to translate this knowledge into novel treatments for BPD. Inspired by reports of abnormal glucose metabolism in mood disorders and by the literature on nervous tissue disease mechanisms in diabetes mellitus, the proposed project tests the novel hypothesis that a specific abnormality of glucose metabolism that has been linked to diabetic neuropathy is a mechanism of brain disease underlying illness severity and treatment resistance in individuals with BPD. Specifically, the project aims to determine whether increased conversion of glucose by aldose reductase through the polyol pathway to sorbitol--a potentially neurotoxic metabolite--is a mechanism of the brain white matter disease that has been associated with treatment resistance and poorer outcome in BPD. The research design involves four groups of twenty nondiabetic individuals. Subjects with bipolar type I mood disorder with severe, treatment resistant illness will be compared to bipolar I subjects with treatment responsive illness and to schizophrenic and normal control subjects. The groups will be compared primarily on three indices: cerebrospinal fluid (CSF) sorbitol concentration, brain white matter disease burden, and the correlation between the first two variables. Methods include structured interview and rating scale administration to determine diagnosis and illness severity; lumbar puncture to withdraw CSF; gas chromatography-mass spectrometry (GC-MS) to measure CSF sorbitol and other metabolites; and magnetic resonance imaging, tissue segmentation, and volumetric analysis to identify and quantify white matter hyperintensities (WMHs). If the research supports the hypothesis, it could provide the rationale to test a completely novel pharmacotherapy for treatment resistant BPD--sorbitol-owering, aldose reductase inhibitor drugs, currently in diabetic neuropathy trials in the U.S. Such treatments could have the potential not only to provide symptom relief but also to repair and prevent the brain disease contributing to treatment resistance.